DRUGS UPON MYOCARDIAL HYPOXIA

描述：格罗斯博士和他的研究团队的这份申请是 与确定心肌缺血机制有关， 预处理 更具体地说，调查人员将确定 KATP在介导预适应中的作用及其与其他神经递质的相互作用 信号通路 他们的首要目标是确定预处理是否 (PC)由缺血、缺氧、KATP开放剂或腺苷共享产生 常见的血液动力学或电生理（EP）机制。 他们将 确定非选择性阻滞剂（格列本脲）、缺血 选择性阻滞剂（5-HD）或血管选择性阻滞剂， 预处理 他们还将确定一个假定的 胰腺选择性KATP阻滞剂预处理。 他们将 确定APD缩短在介导预适应中的重要性。 这将通过确定腺苷或PCO或APD的影响来完成 预处理前后。 它们也将决定 IKr阻断剂，将消除APD缩短效应， 预处理等，在预处理。 在aim 2中，他们将 确定PC产生的受体或信号转导途径 局部缺氧。 他们将决定PKC-α-1的作用 相互作用，cAMP（通过儿茶酚胺），腺苷，最后，如果KATP 是由PKC激活产生的末端效应物。 这将使用 低氧缓冲液（4 × 5分钟）。 他们会使用各种激动剂 和KATP、腺苷、PKA、PKC的拮抗剂，以确定它们的 重要性 在目标III中，他们将确定是否增加腺苷 释放器负责触发PC，如果KATP开启器工作 通过增强腺苷的释放。 这将通过缺氧来完成 或如其它目的中所述的局部缺血。 将测量腺苷 使用微透析技术。 在目标IV中，申请人将确定 如果KATP开放剂或腺苷激动剂降低PC阈值， 腺苷或PKC或KATP介导记忆（PC可以在多长时间后 保护被看到了吗？）。 他们还将决定伊藤在 心脏记忆 他们将使用PKC抑制剂，KATP阻断剂，腺苷 拮抗剂，4-氨基吡啶。

DESCRIPTION: This application for Dr. Gross and his research team is concerned with the determination of the mechanism of myocardial preconditioning. More specifically, the investigators will determine the role of KATP in mediating preconditioning and its interaction with other signaling pathways. Their first aim is to determine if preconditioning (PC) produced by ischemia, hypoxia, KATP openers or adenosine share common hemodynamic or electrophysiologic (EP) mechanisms. They will determine the effect of a nonselective blocker (glyburide), an ischemia selective blocker (5-HD), or a vascular selective blocker on preconditioning. They will also determine the effect of a putative pancreatic selective KATP blocker on preconditioning. They will determine the importance of APD shortening in mediating preconditioning. This will be done by determining the effect of adenosine or PCO or APD before and after preconditioning. They will also determine the effect of IKr blockers which will abolish the APD shortening effects of preconditioning, etc., on preconditioning. In aim II, they will determine the receptor or signal transduction pathways for PC produced by regional hypoxia. They will determine the role of PKC-alpha-1 interactions, cAMP (via catecholamines), adenosine, and finally if KATP is the end effector produced by PKC activation. This will be done using hypoxic buffer (4X5 min) in dogs. They will use a variety of agonists and antagonists of KATP, adenosine, PKA, PKC to determine their importance. In aim III, they will determine if increased adenosine release is responsible for triggering PC and if KATP openers work through enhancing adenosine release. This will be done using hypoxia or ischemia as described in other aims. Adenosine will be measured using a microdialysis technique. In aim IV the applicant will determine if KATP openers or adenosine agonists lower PC threshold and if adenosine or PKC or KATP mediate memory (how long after PC can protection be seen?). They will also determine the role of Ito in cardiac memory. They will use PKC inhibitors, KATP blockers, adenosine antagonists, 4-aminopyridine.